Displaying publications 1 - 20 of 139 in total

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  1. Cheung DH, Samoh N, Jonas K, Lim SH, Kongjareon Y, Guadamuz TE
    Sex Transm Dis, 2024 May 01;51(5):352-358.
    PMID: 38301623 DOI: 10.1097/OLQ.0000000000001937
    BACKGROUND: Human immunodeficiency virus (HIV) testing for Thai men who have sex with men (MSM) is suboptimal, which undermines their linkage to care and subsequent HIV preexposure prophylaxis (PrEP) uptake.

    METHODS: We analyzed a cross-sectional survey conducted in 2021 among Thai MSM who attended any private sex parties or circuit parties in the past 3 years ("sexualized parties").

    RESULTS: Of the 424 men included in our analysis, 47.6% had been recently tested for HIV in the past 1 year, 30.2% had not recently been tested, and 22.2% had never been tested. In our multivariable analysis, relative to participants who had recently tested for HIV, those who have never tested were more likely to have lower education or to live outside of Bangkok, and to have attended both circuit and private sex parties (vs. private sex party only) but were less likely to report any sexually transmitted infection diagnosis or to have heard of PrEP. Participants who had an HIV test more than a year ago were more likely to have attended both circuit and private sex parties (vs. private sex parties only) but were less likely to have any sexually transmitted infection diagnosis, meet sexual partners online, or have heard of PrEP. Rates of condomless anal sex and willingness to use PrEP were similar across groups.

    CONCLUSIONS: Despite the high rates of sexual risk-taking, sexualized party attendees reported suboptimal HIV testing uptake. The joint promotion of HIV testing and PrEP is warranted-especially on-premise HIV testing at circuit parties and outreach at online platforms to reach sexualized party attendees.

  2. Inoue Y, Tiamkao S, Zhou D, Cabral-Lim L, Lim KS, Lim SH, et al.
    Epilepsia Open, 2024 Apr 04.
    PMID: 38576178 DOI: 10.1002/epi4.12929
    OBJECTIVE: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS).

    METHODS: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs.

    RESULTS: In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p 

  3. Lim SH, Wong TW, Tay WX
    Adv Colloid Interface Sci, 2024 Mar;325:103094.
    PMID: 38359673 DOI: 10.1016/j.cis.2024.103094
    Nanoparticles as cancer therapeutic carrier fail in clinical translation due to complex biological environments in vivo consisting of electrolytes and proteins which render nanoparticle aggregation and unable to reach action site. This review identifies the desirable characteristics of nanoparticles and their constituent materials that prevent aggregation from site of administration (oral, lung, injection) to target site. Oral nanoparticles should ideally be 75-100 nm whereas the size of pulmonary nanoparticles minimally affects their aggregation. Nanoparticles generally should carry excess negative surface charges particularly in fasting state and exert steric hindrance through surface decoration with citrate, anionic surfactants and large polymeric chains (polyethylene glycol and polyvinylpyrrolidone) to prevent aggregation. Anionic as well as cationic nanoparticles are both predisposed to protein corona formation as a function of biological protein isoelectric points. Their nanoparticulate surface composition as such should confer hydrophilicity or steric hindrance to evade protein corona formation or its formation should translate into steric hindrance or surface negative charges to prevent further aggregation. Unexpectedly, smaller and cationic nanoparticles are less prone to aggregation at cancer cell interface favoring endocytosis whereas aggregation is essential to enable nanoparticles retention and subsequent cancer cell uptake in tumor microenvironment. Present studies are largely conducted in vitro with simplified simulated biological media. Future aggregation assessment of nanoparticles in biological fluids that mimic that of patients is imperative to address conflicting materials and designs required as a function of body sites in order to realize the future clinical benefits.
  4. Tan YS, Ng MP, Tan CH, Tang WK, Sim KS, Yong KT, et al.
    J Nat Prod, 2024 Feb 23;87(2):286-296.
    PMID: 38284153 DOI: 10.1021/acs.jnatprod.3c00960
    Nine new alkaloids, eugeniinalines A-H (1-8) and (+)-eburnamenine N-oxide (9), comprising one quinoline, six indole, and two isogranatanine alkaloids, were isolated from the stem-bark extract of the Malayan Leuconotis eugeniifolia. The structures and absolute configurations of these alkaloids were established based on the analysis of the spectroscopic data, GIAO NMR calculations, DP4+ probability analysis, TDDFT-ECD method, and X-ray diffraction analysis. Eugeniinaline A (1) represents a new pentacyclic quinoline alkaloid with a 6/6/5/6/7 ring system. Eugeniinaline G (7) and its seco-derivative, eugeniinaline H (8), were the first isogranatanine alkaloids isolated as natural products. The known alkaloids leucolusine (10) and melokhanine A (11) were found to be the same compound, based on comparison of the spectroscopic data of both compounds, with the absolute configuration of (7R, 20R, 21S). Eugeniinalines A and G (1 and 7) showed cytotoxic activity against the HT-29 cancer cell line with IC50 values of 7.1 and 7.2 μM, respectively.
  5. Lim SH, Lim YC, Zaki RA, Johari BM, Chang CY, Omar SFS, et al.
    PLoS One, 2024;19(4):e0298376.
    PMID: 38626017 DOI: 10.1371/journal.pone.0298376
    BACKGROUND: Post Acute COVID Syndrome (PACS), a complex and poorly understood condition characterised by persistent symptoms following the acute phase of COVID-19 infection, has emerged as a significant global health concern. Healthcare workers who had been at the forefront of the pandemic response are at heightened risk of contracting the virus and subsequently developing PACS. Therefore, we aim to determine the prevalence and risk factors for PACS among healthcare workers infected with COVID-19.

    METHODS: A cross-sectional study was conducted between October 2022 and August 2023 using an online REDCap electronic data capture tool questionnaire. PACS was defined as new or persistent symptoms lasting more than 28 days after a positive SARS-CoV-2 polymerase chain reaction or rapid test kit antigen test. Multivariable logistic regression was performed to determine predictors associated with PACS.

    RESULTS: Among 609 infected healthcare workers, they were predominantly female (71.8%), Malays (84.6%), and aged 18-39 years (70.1%). 50.7% of infected healthcare workers experienced PACS. The most common PACS symptoms experienced were fatigue (27.9%), cough (25.1%), decreased physical strength (20.5%), and musculoskeletal pain (19.2%). Those who are more likely to develop PACS were females, underlying asthma, and COVID-19 severity category 3. On the other hand, those who received booster vaccinations were less likely to develop PACS.

    CONCLUSION: PACS is prevalent among healthcare workers with COVID-19 at the University Malaya Medical Centre. These findings emphasise the critical need for those with higher risk to receive regular health monitoring and checkups to detect any early signs of PACS. It underscores the need for continuous support and healthcare interventions to mitigate the impacts of PACS and ensure the physical and mental well-being of healthcare workers.

  6. Gautam K, Paudel K, Jacobs J, Wickersham JA, Ikhtiaruddin WM, Azwa I, et al.
    JMIR Form Res, 2023 Aug 24;7:e48113.
    PMID: 37616034 DOI: 10.2196/48113
    BACKGROUND: Chemsex-the use of psychoactive drugs to enhance the sexual experience-is an increasing phenomenon globally. Despite the increasing burden and associated harms of chemsex, evidence-based interventions (ie, behavioral and pharmacological) for chemsex users are nonexistent.

    OBJECTIVE: In this study, we assessed the usability and acceptability of a mobile health (mHealth)-delivered safer chemsex package ("PartyPack") as a sexual harm reduction strategy among men who have sex with men in Malaysia-a setting where chemsex is becoming increasingly prevalent.

    METHODS: This study is part of a larger smartphone app-based intervention (ie, JomPrEP; University of Connecticut) designed to improve access to HIV prevention services among Malaysian men who have sex with men. A total of 50 participants were recruited from the Greater Kuala Lumpur region of Malaysia to use the JomPrEP app, which included a feature allowing participants to order PartyPack, for 30 days (March-April 2022). The usability and acceptability of the PartyPack were assessed using self-report, app analytics, and exit interviews (n=20).

    RESULTS: Overall, 8% (4/50) of participants reported having engaged in chemsex in the past 6 months; however, engagement in condomless sex (34/50, 68%) and group sex (9/50, 18%) was much higher. A total of 43 (86%) participants ordered PartyPack, of which 27 (63%) made multiple orders during the 30 days. Most participants (41/43, 95%) reported being satisfied with the PartyPack order feature in the app, with 91% (39/43) indicating the order and tracking process was easy. Thematic data exploration further revealed important information for understanding (eg, items included in the package, use of mHealth platform to order package, and discreetness of the PartyPack box and order and delivery) and refining the logistical preferences (eg, using branded items and allowing customization during order).

    CONCLUSIONS: Our findings provide strong evidence of the usability and acceptability of a mHealth-delivered safer chemsex package as a potential sexual harm reduction tool among this underserved population. Replication in a study with a larger sample size to test the efficacy of the PartyPack is warranted.

  7. Earnshaw VA, Cox J, Wong PL, Saifi R, Walters S, Azwa I, et al.
    AIDS Behav, 2023 Jul;27(7):2103-2112.
    PMID: 36472685 DOI: 10.1007/s10461-022-03942-9
    Stigma in healthcare settings is a pernicious barrier to HIV prevention and treatment in contexts with strong HIV-related structural stigma. Previous work has documented substantial stigma towards key populations and people living with HIV (PLWH) among Malaysian doctors. The perspectives of Malaysian key populations and PLWH, however, remain understudied. In 2021, 34 Malaysian participants representing key populations and PLWH engaged in a photovoice study designed to qualitatively explore their experiences with and hopes for doctor interactions. Many participants reported stigma from their doctors, perceiving that doctors view them as not normal, sinful, misguided, and incapable. Several emphasized that they wear figurative masks to conceal aspects of themselves from doctors. Yet, many also remain hopeful for constructive relationships with doctors. They want their doctors to know that they are bright, capable, kind, and valuable. Interventions are needed to address stigma among doctors working in contexts with strong structural stigma.
  8. Earnshaw VA, Cox J, Wong PL, Saifi R, Walters S, Azwa I, et al.
    AIDS Behav, 2023 Jul;27(7):2055-2069.
    PMID: 36463390 DOI: 10.1007/s10461-022-03938-5
    Photovoice is an action-oriented qualitative method involving photography and story-telling. Although photovoice yields a powerful form of data that can be leveraged for research, intervention, and advocacy, it has arguably been underutilized within HIV research. Online, asynchronous photovoice methods represent a promising alternative to traditional in-person methods, yet their acceptability and feasibility with key populations and people living with HIV (PLWH) have yet to be explored. The current study describes the methods and evaluation of an online, asynchronous photovoice project conducted with 34 members of key populations and PLWH in Malaysia in 2021. A HIPAA-compliant website incorporating a series of instructional videos was created to facilitate participant engagement and data collection. Quantitative and qualitative indicators suggest that participants found the project to be highly acceptable and feasible. Online, asynchronous photovoice methods hold potential for increasing the scale of this powerful and versatile qualitative research method with key populations and PLWH.
  9. Lee YL, Zaini AA, Idris AN, Abdullah RA, Wong JS, Hong JS, et al.
    J Paediatr Child Health, 2023 Jul;59(7):879-884.
    PMID: 37066819 DOI: 10.1111/jpc.16405
    AIMS: Knowledge on the spectrum of thyroid disorders amongst Turner syndrome (TS) patients in Southeast Asia is limited. This study aimed to evaluate the prevalence of thyroid autoimmunity, the spectrum of autoimmune thyroid disease and association with age and karyotype amongst Malaysian TS girls.

    METHODS: A cross-sectional study was conducted at 11 paediatric endocrine units in Malaysia. Blood samples for antithyroglobulin antibodies, antithyroid peroxidase antibodies and thyroid function test were obtained. In patients with pre-existing thyroid disease, information on clinical and biochemical thyroid status was obtained from medical records.

    RESULTS: Ninety-seven TS patients with a mean age of 13.4 ± 4.8 years were recruited. Thyroid autoimmunity was found in 43.8% of TS patients. Nineteen per cent of those with thyroid autoimmunity had autoimmune thyroid disease (Hashimoto thyroiditis in 7.3% and hyperthyroidism in 1% of total population). Patients with isochromosome X and patients with 45,X mosaicism or other X chromosomal abnormalities were more prone to have thyroid autoimmunity compared to those with 45,X karyotype (OR 5.09, 95% CI 1.54-16.88, P = 0.008 and OR 3.41, 95% CI 1.32-8.82, P = 0.01 respectively). The prevalence of thyroid autoimmunity increased with age (33.3% for age 0-9.9 years; 46.8% for age 10-19.9 years and 57.1% age for 20-29.9 years) with autoimmune thyroid disease detected in 14.3% during adulthood.

    CONCLUSION: Thyroid autoimmunity was significantly associated with the non 45,X karyotype group, particularly isochromosome X. Annual screening of thyroid function should be carried out upon diagnosis of TS until adulthood with more frequent monitoring recommended in the presence of thyroid autoimmunity.

  10. Tang SY, Tan CH, Sim KS, Yong KT, Lim KH, Low YY, et al.
    Phytochemistry, 2023 Apr;208:113587.
    PMID: 36646163 DOI: 10.1016/j.phytochem.2023.113587
    Eight undescribed iboga alkaloids, polyneurines A-H, were isolated from the bark of Tabernaemontana polyneura. The structures of these alkaloids were established by interpretation of the MS and NMR data, while the configurations were determined using GIAO NMR calculations and DP4+ probability analysis, TDDFT-ECD method, or X-ray diffraction analysis. Polyneurine A possesses a γ-lactone unit embedded within the iboga skeleton, while polyneurines D and E incorporate a formylmethyl moiety at C-3 of the iboga skeleton. Biosynthetic pathways towards the formation of polyneurines A, C, D, and E were proposed.
  11. Lim SH, Tan TL, Ngo PW, Lee LY, Ting SY, Tan HJ
    Med J Malaysia, 2023 Mar;78(2):241-249.
    PMID: 36988537
    INTRODUCTION: Time is the greatest challenge in stroke management. This study aimed to examine factors contributing to prehospital delay and decision delay among stroke patients.

    MATERIALS AND METHODS: A cross-sectional study involving acute stroke patients admitted to Seri Manjung Hospital was conducted between August 2019 and October 2020 via faceto- face interview. Prehospital delay was defined as more than 120 minutes taken from recognition of stroke symptoms till arrival in hospital, while decision delay was defined as more than 60 minutes taken from recognition of stroke symptoms till decision was made to seek treatment.

    RESULTS: The median prehospital delay of 102 enrolled patients was 364 minutes (IQR 151.5, 1134.3) while the median for decision delay was 120 minutes (IQR 30.0, 675.0). No history of stroke (adj. OR 4.15; 95% CI 1.21, 14.25; p=0.024) and unaware of thrombolysis service (adj. OR 17.12; 95% CI 1.28, 229.17; p=0.032) were associated with higher odds of prehospital delay, while Indian ethnicity (adj. OR 0.09; 95% CI 0.02, 0.52; p=0.007) was associated with lower odds of prehospital delay as compared to Malay ethnicity. On the other hand, higher National Institutes of Health Stroke Scale (NIHSS) score (adj. OR 0.86; 95% CI 0.78, 0.95; p=0.002) was associated with lower odds of decision delay.

    CONCLUSION: Public awareness is crucial to shorten prehosital delay and decision delay for better patients' outcomes in stroke. Various public health campaigns are needed to improve the awareness for stroke.

  12. Lim SH, Chin NL, Sulaiman A, Tay CH, Wong TH
    Foods, 2023 Jan 31;12(3).
    PMID: 36766121 DOI: 10.3390/foods12030592
    The safety, shelf life, and quality of fresh cow milk treated using industrial High-Pressure Processing (HPP) treatment at 600 MPa for 10 min was studied to identify the novelty of this non-thermal technology in milk processing. Changes in microbiological and physicochemical properties, including nutritional values of vitamins and amino acid profiles, were measured for a 60-day storage period at 6 °C +/- 1 °C. The HPP treatment produced milk that met all microbial safety requirements and exhibited a shelf life beyond 60 days in a hot and humid region. High physicochemical stability was achieved, with consistent pH and undetectable titratable acidity. The HPP treatment successfully retained all vitamins and minerals, including calcium (99.3%), phosphorus (99.4%), and magnesium (99.1%). However, the 60-day storage caused some degradation of Vitamin A (25%), B3 (91%), B5 (35%), B6 (80%), and C (85%), and minerals, including potassium (5%) and zinc (18%) when compared with fresh milk. This research has shown that the adoption of advanced treatment with HPP is very beneficial to the dairy industry in preserving milk quality in terms of its physicochemical and nutritional properties and extending its storage shelf life beyond 60 days.
  13. Tan YS, Wong SK, Yong KT, Lim KH, Lim SH, Low YY
    J Nat Prod, 2023 Jan 27;86(1):232-236.
    PMID: 36651825 DOI: 10.1021/acs.jnatprod.2c00731
    Eugeniifoline (1), a pentacyclic indole alkaloid with a five-membered ring E, was isolated for the first time as a natural product from the stem-bark extract of Leuconotis eugeniifolia. Eugeniifoline (1) was previously reported as a synthetic product from a diversity-enhanced extract, but with the configuration at C-21 reported as S (1a). The configuration at C-21 was revised to R as shown in 1, based on the NOE data, GIAO NMR calculations, and DP4+ probability analysis, as well as the TDDFT-ECD method.
  14. Subermaniam K, Lew SY, Yow YY, Lim SH, Yu WS, Lim LW, et al.
    Iran J Basic Med Sci, 2023;26(6):669-679.
    PMID: 37275754 DOI: 10.22038/IJBMS.2023.67835.14842
    OBJECTIVES: Neuroinflammation and microglial activation are pathological features in central nervous system disorders. Excess levels of reactive oxygen species (ROS) and pro-inflammatory cytokines have been implicated in exacerbation of neuronal damage during chronic activation of microglial cells. Padina australis, a brown macroalga, has been demonstrated to have various pharmacological properties such as anti-neuroinflammatory activity. However, the underlying mechanism mediating the anti-neuroinflammatory potential of P. australis remains poorly understood. We explored the use of Malaysian P. australis in attenuating lipopolysaccharide (LPS)-stimulated neuroinflammation in BV2 microglial cells.

    MATERIALS AND METHODS: Fresh specimens of P. australis were freeze-dried and subjected to ethanol extraction. The ethanol extract (PAEE) was evaluated for its protective effects against 1 µg/ml LPS-stimulated neuroinflammation in BV2 microglial cells.

    RESULTS: LPS reduced the viability of BV2 microglia cells and increased the levels of nitric oxide (NO), prostaglandin E2 (PGE2), intracellular reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). However, the neuroinflammatory response was reversed by 0.5-2.0 mg/ml PAEE in a dose-dependent manner. Analysis of liquid chromatography-mass spectrometry (LC-MS) of PAEE subfractions revealed five compounds; methyl α-eleostearate, ethyl α-eleostearate, niacinamide, stearamide, and linoleic acid.

    CONCLUSION: The protective effects of PAEE against LPS-stimulated neuroinflammation in BV2 microglial cells were found to be mediated by the suppression of excess levels of intracellular ROS and pro-inflammatory mediators and cytokines, denoting the protective role of P. australis in combating continuous neuroinflammation. Our findings support the use of P. australis as a possible therapeutic for neuroinflammatory and neurodegenerative diseases.

  15. Maviglia F, Wickersham JA, Azwa I, Copenhaver N, Kennedy O, Kern M, et al.
    PMID: 36612617 DOI: 10.3390/ijerph20010294
    Background: Chemsex is the use of illicit drugs—particularly methamphetamine, gamma hydroxybutyrate (GHB), and gamma-butyrolactone (GBL)—to enhance sexual activity. Chemsex, which occurs primarily among communities of men who have sex with men (MSM), is associated with greater HIV risk behaviors, including multiple sex partners, group sex, condomless sex, and injection drug use. Despite evidence showing chemsex engagement among Malaysian MSM, there is a paucity of research on chemsex among MSM in Malaysia. Methods: This cross-sectional study was conducted through an online survey (August to September 2021) among 870 Malaysian MSM. Participants were recruited through targeted advertisements on social networks. We collected information regarding participants’ recent (<6 months) engagement in chemsex, demographic characteristics, psychosocial factors, pre-exposure prophylaxis (PrEP) knowledge and history, and recent sexual- and drug-related behavior. Multivariable logistic regression was used to identify factors associated with recent (<6 months) chemsex engagement. Results: Just under 1 in 10 (9.0%) of participants reported having engaged in chemsex in the previous six months. More than two-thirds of participants (69.1%) had not disclosed their sexual orientation to anyone in their family and 35.2% reported moderate to severe depressive symptoms. Multivariable analysis found that recent injection drug use (adjusted odds ratio: aOR = 6.61; 95% confidence interval: CI, 2.30−19.03), having shared pre-exposure prophylaxis (PrEP) with someone else (aOR = 5.60; 95% CI, 1.76−17.77), higher perceived HIV risk (aOR = 3.15; 95% CI, 1.25−7.93), knowing someone using PrEP (aOR = 2.93; 95% CI, 1.62−5.31), recent engagement in transactional sex (aOR = 2.38; 95% CI, 1.06−5.39), having a recent STI diagnosis (aOR = 2.36; 95% CI, 1.25−4.44), recent engagement in anal sex (aOR = 2.21; 95% CI, 1.07−4.57), and recent sexual intercourse with an HIV-positive partner (aOR = 2.09; 95% CI, 1.07−4.08) were associated with recent engagement in chemsex. Conclusions: Malaysian MSM who practice chemsex are vulnerable to several HIV risk factors, such as transactional sex, HIV-positive sexual partners, and injection drug use. There is an urgent need for programs that integrate drug, sexual health, and mental health services, with a focus on harm reduction (e.g., condoms, access to and utilization of HIV testing and PrEP services, drug knowledge, and safer drug use) tailored for MSM who practice chemsex.
  16. Alkhoori MA, Kong AS, Aljaafari MN, Abushelaibi A, Erin Lim SH, Cheng WH, et al.
    Biomolecules, 2022 Nov 03;12(11).
    PMID: 36358976 DOI: 10.3390/biom12111626
    Date palm (Phoenix dactylifera L.) is an essential agricultural crop in most Middle Eastern countries, and its fruit, known as dates, is consumed by millions of people. Date seeds, a by-product of the date fruit processing industry, are a waste product used as food for domestic farm animals. Date seeds contain abundant sources of carbohydrates, oil, dietary fiber, and protein; they also contain bioactive phenolic compounds that may possess potential biological properties. In addition, its rich chemical composition makes date seeds suitable for use in food product formulation, cosmetics, and medicinal supplements. This review aims to provide a discourse on the nutritional value of date seeds. The latest data on the cytotoxicity of date seed compounds against cancer cell lines, its ability to combat diabetes, antioxidant potential, antimicrobial effect, and anti-inflammatory activity will be provided, considering its potential to be a nutritional therapeutic agent for chronic diseases. Application of date seeds in the form of powder and oil will also be discussed.
  17. Tan CH, Sim DSY, Lim SH, Mohd Mohidin TB, Mohan G, Low YY, et al.
    Planta Med, 2022 Nov;88(14):1325-1340.
    PMID: 35100653 DOI: 10.1055/a-1755-5605
    Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the β-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.
  18. Ang BH, Ho WK, Wijaya E, Kwan PY, Ng PS, Yoon SY, et al.
    J Clin Oncol, 2022 May 10;40(14):1542-1551.
    PMID: 35143328 DOI: 10.1200/JCO.21.01647
    PURPOSE: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women.

    METHODS: In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration.

    RESULTS: Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non-BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% (P value = .003), thereby improving the overall efficacy.

    CONCLUSION: Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.

  19. Breast Cancer Association Consortium, Mavaddat N, Dorling L, Carvalho S, Allen J, González-Neira A, et al.
    JAMA Oncol, 2022 Mar 01;8(3):e216744.
    PMID: 35084436 DOI: 10.1001/jamaoncol.2021.6744
    IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.

    OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

    DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

    EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

    MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

    RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

    CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

  20. Ho WK, Tai MC, Dennis J, Shu X, Li J, Ho PJ, et al.
    Genet Med, 2022 Mar;24(3):586-600.
    PMID: 34906514 DOI: 10.1016/j.gim.2021.11.008
    PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.

    METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).

    RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.

    CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

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